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More Time With Low CD4 Count Boosts Non-AIDS Cancer Risk
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5th IAS Conference on HIV Pathogenesis, Treatment and Prevention, July 19-22, 2009, Cape Town
Mark Mascolini
Every year spent with a CD4 count under 200 independently raised the risk of a non-AIDS cancer diagnosis in the Dutch ATHENA cohort [1]. More time spent with 200 to 350 CD4s also boosted the non-AIDS cancer risk, but that correlation stopped short of statistical significance. Non-AIDS cancers with an infectious origin drove the association between a low CD4 count and cancer risk, a finding supporting thinking that longer time with a compromised immune system makes cancer more likely.
ATHENA investigators studied 9595 people starting a potent antiretroviral combination after January 1, 1996. Cohort participants could have tried single- or double-drug antiretroviral regimens before then. Follow-up began when cohort members started their first triple regimen and continued until their last available CD4 count and viral load. The investigators noted that the "vast majority" of cancer diagnoses in the Netherlands are histologically confirmed. The analysis excluded basal cell carcinoma and squamous cell carcinoma of the skin.
The study cohort included 11,459 people, 77% of them men, 63% born in Western Europe, 85% infected during sex, and 5% infected while injecting drugs. Median lowest-ever CD4 count was 150, and initial viral load was 80,000 copies. Almost three quarters of cohort members ever smoked, but only 7% were alcohol abusers. The investigators did not have data on smoking and alcohol use from all cohort members.
Kesselring counted 232 non-AIDS cancer diagnoses during 67,179 person-years of follow-up, including 44 lung cancers, 37 anal cancers, 20 Hodgkin lymphomas, 20 larynx cancers, 17 hematologic cancers, 16 prostate cancers, 16 liver cancers, 12 breast cancers, 10 colon cancers, and numerous other cancers. A high proportion of diagnosed cancers, 43%, could be attributed to infectious causes.
Median CD4 count 6 months before non-AIDS cancer diagnosis stood at 340 (interquartile range 210 to 540), 205 people (89%) were taking combination antiretrovirals when diagnosed with cancer, and 169 people (75%) had an undetectable viral load at cancer diagnosis. While 120 people diagnosed with cancer (77%) smoked, 17 (7%) had HCV infection and 14 (6%) had HBV infection.
To estimate the impact of HIV-related and non-HIV variables on non-AIDS cancer risk, Kesselring and collaborators factored in both time-dependent variables (age, exposure to combination antiretrovirals, latest CD4 count, cumulative time with a CD4 count below 200, 350, or 500, latest viral load, cumulative time at viral load above 400 copies) and fixed variables (lowest-ever CD4 count, CD4 count at start of triple antiretroviral therapy, duration of HIV infection, gender, region of origin, mode of HIV transmission, prior non-AIDS-defining cancers, prior AIDS, alcohol use, smoking history, coinfection with HBV or HCV).
This analysis determined that every year with a CD4 count under 200 independently raised the non-AIDS cancer risk about 10% (P = 0.03). There was also a strong trend toward non-AIDS cancer diagnosis for every additional year with a CD4 count between 200 and 350 (P = 0.09). Every year with a CD4 count under 200 independently raised the risk of non-AIDS infection-related cancers about 20% (P = 0.01) but had no significant impact on other non-AIDS cancers. The trend linking time spent with 200 to 350 CD4s and infection-related cancers fell short of statistical significance (P = 0.13).
Every additional 10 years of age (P < 0.0001) and HBV coinfection (P = 0.02) nearly doubled the risk of non-AIDS cancer, and a previous AIDS diagnosis upped the risk about 40% (P = 0.03). Time spent with a viral load above 400 copies did not independently predict cancer. Compared with Western European natives, those from other regions had almost a 50% lower risk of non-AIDS cancer (P = 0.006).
A recent Australian study supports the CD4-cancer correlation in ATHENA by tracing links between a compromised immune system and non-AIDS cancer risk in people with HIV and in organ transplant patients [2]. Among the 28 cancers analyzed, 20 arose significantly more often in the two immunocompromised groups than in the general population and 17 occurred significantly more often in people with HIV. Because most of the cancers diagnosed more often in immunocompromised people had an infectious cause, the investigators proposed that a weakened immune system spurred development of these cancers.
References
1. Kesselring A, Gras L, Smit C, et al. Longer duration of exposure to immunodeficiency and detectable viremia both are risk factors for non-AIDS defining malignancies in HIV-1 infected patients on combination antiretroviral therapy. 5th IAS Conference on HIV Pathogenesis, Treatment and Prevention. July 19-22, 2009. Cape Town. Abstract WEAB104.
2. Grulich AE, van Leeuwen MT, Falster MO, Vajdic CM. Incidence of cancers in people with HIV/AIDS compared with immunosuppressed transplant recipients: a meta-analysis. Lancet. 2007;370:59-67.
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